The chemical entity (2S)-2-[(1S)-1-carbethoxybutylamino]-1-oxopropyl-(2S,3aS,7aS)-perhydroindole-2-carboxylic acid of formula (I), known generically as perindopril
and its pharmaceutically acceptable salts, specially salt of perindopril with tertiary butyl amine i. e. perindopril erbumine of formula (II)
are therapeutically valuable ACE Inhibitors, useful for the treatment of hypertension.
The drug is commercially sold: as the erbumine salt and was approved in the USA on Dec. 30, 1993 for the treatment of hypertension. The final printed label of the approved drug, ACEON® Tablets states that perindopril erbumine is a white, crystalline powder with a molecular weight of 368.47 (free acid) or 441.61 (salt form) and freely soluble in water (60% w/w), alcohol and chloroform.
Several methods are known for preparation of perindopril and perindopril erbumine as well as methods for preparation of compounds useful as intermediates for preparation of perindopril and perindopril erbumine. A brief summary of such methods are given hereinbelow:
U.S. Pat. No. 4,508,729, which is the product patent of perindopril, discloses a method for preparation of perindopril monoammonium salt, as a mixture of two diastereomers, involving reductive amination of (2S)-1-[(S)-alanyl]-2-carboxyperhydroindole with pyruvic acid in the presence of sodium cyanoborohydride. The (2S)-1-[(S)-alanyl]-2-carboxyperhydroindole, in turn is prepared by reaction of (2S)-2-ethoxycarbonylperhydroindole with L-BOC.-alanine to give (2S)-N-[(S)-BOC.-alanyl]-2-ethoxycarbonylperhydroindole, which on step-wise removal of the carboxyl and amino protecting groups gives (2S)-1-[(S)-alanyl]-2-carboxyperhydroindole. The synthesis is schematically represented hereinbelow.

However, this method gives perindopril as a mixture of two diastereomers, of which only one is a therapeutic. Further, there is neither any enabling disclosure in the patent as to how the diastereomers are separated to give perindopril, having the desired (S) configuration for all the five chiral centers in the molecule nor any method is disclosed as to how the tert-butylamine salt i. e. perindopril erbumine can be prepared.
Moreover, the method involves protection of the amino group of the alanine moiety as the t-BOC group, which necessitates use of corrosive trifluoroacetic acid for its subsequent removal, thereby rendering the method industrially unattractive.
U.S. Pat. No. 4,902,817 discloses a stereoselective process for the industrial synthesis of N-[(S)-1-carbethoxybutyl]-(S)-alanine comprising reaction of ethyl-L-norvalinate hydrochloride with pyruvic acid under catalytic hydrogenation conditions. The N-[(S)-1-carbethoxybutyl]-(S)-alanine thus obtained is a key intermediate for perindopril. The synthesis is schematically represented hereinbelow.

However, this patent does not provide any enabling method for preparation of perindopril or perindopril erbumine from N-[(S)-1-carbethoxybutyl]-(S)-alanine thus obtained.
EP 0 309 324 discloses another method for synthesis of (S,S) diastereoisomer of N-[(S)-1-carbethoxybutyl]-(S)-alanine, a key intermediate for perindopril comprising reaction of L-alanine benzyl ester p-toluenesulfonate with ammonia to form the free base, which is condensed with ethyl α-bromo valerate to give a racemic mixture of N-[(S)-1-carbethoxybutyl]-(S)-alanine and N-[(R)-1-carbethoxybutyl]-(S)-alanine. The (S) isomer is separated by resolution with maleic acid and subsequent removal of the benzyl ester group provides the (S,S) diastereoisomer of N-[(S)-1-carbethoxybutyl]-(S)-alanine, which can be further elaborated to perindopril and perindopril erbumine.

However, this patent, also does not provide any enabling method for preparation of perindopril or perindopril erbumine from N-[(S)-1-carbethoxybutyl]-(S)-alanine thus obtained.
WO 01/56353 discloses yet another method for preparation of the (S,S) diastereoisomer of N-[(S)-1-carbethoxybutyl]-(S)-alanine, a key intermediate for perindopril comprising reacting sodium pyruvate with L-norvaline ester under reducing conditions using palladium carbon as catalyst.

However, this patent, also does not provide any enabling method for preparation of perindopril or perindopril erbumine from N-[(S)-1-carbethoxybutyl]-(S)-alanine thus obtained.
WO 01/56972 discloses a further method for preparation of the (S,S) diastereoisomer of N-[(S)-1-carbethoxybutyl]-(S)-alanine, a key intermediate for perindopril comprising reacting 1-alanine and ethyl 2-oxo-pentanoic acid under catalytic hydrogenation conditions and isolating the product at a pH between 3to 3.5, followed by crystallization.

However, this patent, also does not provide any enabling method for preparation of perindopril or perindopril erbumine from N-[(S)-1-carbethoxybutyl]-(S)-alanine thus obtained.
EP 1 256 590 discloses a process for preparation of (2S, 3aS, 7aS)-1-(S)-alanyl-octahydro-1H-indole-2-carboxylic acid, an intermediate for perindopril comprising reaction of (2S)-2,3-dihydroindole-2-carboxylic acid with t-BOC-L-alanine to form the amide compound followed by hydrogenation to give (2S, 3aS, 7aS)-1-(S)-alanyl-octahydro-1H-indole-2-carboxylic acid, which can be further elaborated to perindopril.

However, this patent does not provide any enabling method for preparation of perindopril or perindopril erbumine from (2S, 3aS, 7aS)-1-(S)-alanyl-octahydro-1H-indole-2-carboxylic acid thus obtained.
WO 96/33984 discloses N-sulfoxy anhydrides of N-[1-(S)-ethoxycarbonyl-3-phenylpropyl/butyl-S-alanine, and a process for preparation of several ACE inhibitors including perindopril using the said N-sulfoxy anhydride compounds. The N-sulfoxy anhydride is in turn prepared by reacting the corresponding carboxylic acid compound with N-(chlorosulfinyl)-heterocyclic compound, wherein the heterocycle is an alkyl imidazole, benzimidazole, tetrazole or other similar heterocyclic compounds.

However, this patent application specifically discloses detailed methods for synthesis of trandolapril, but not perindopril.
GB 2 095 252 claims certain N-(substituted aminoalkanoyl) heterocyclic compounds having antihypertensive and ACE Inhibition activity and a process for preparation thereof, which comprises an amide forming reaction of a suitable amine compound and the reactive derivatives of the suitable carboxylic acid compound. The reactive carboxylic derivatives mentioned therein include acyl halides, anhydrides, mixed anhydrides, lower alkyl esters, carbodiimides, carbonyl diimidazoles and the like.

However, this patent disclosure does not include perindopril as the antihypertensive and ACE inhibitory compounds mentioned therein.
DE. 197 21 290 describes a method for preparation of several ACE Inhibitors of formula (D), including perindopril, wherein Z is alkyl or phenyl and R1 is an amino acid as found in commercially valuable ACE inhibitors. The process comprises the steps of first silylating the compound of formula (A) to give the (bis)silyl derivative of formula (B), followed by reaction of compound (B) with thionyl chloride to give the silylated acid chloride derivative of formula (C). Compound (C) is then reacted with the respective amino acid, R1H to give compound of formula (D).

This method is however, lengthy and not cost-effective since there is a step of silylation using expensive silylating agents and subsequent step of desilylation involved.
The first enabling industrial method for preparation of perindopril erbumine was disclosed. in U.S. Pat. No. 4,914,214 comprising reaction of (2S, 3aS,7aS)-2-carboxyperhydroindole, wherein the carboxylic acid at 2-position of the octahydroindole ring is protected as the benzyl group or is esterified with a linear or branched alkyl group, with (S,S) diastereoisomer of N-[(S)-1-carbethoxybutyl]-(S)-alanine in an alkaline medium in the presence of a catalyst, such as dicyclohexylcarbodiimide and in the presence of 1-hydroxybenzotriazole to give perindopril benzyl or alkyl ester. Subsequent deprotection of the carboxylic acid protective group gives perindopril in the form of a base.
The perindopril free base is dissolved in a solvent chosen from lower aliphatic alcohol, acetonitrile, ethyl acetate or dioxane or mixtures thereof and the solution reacted with tert-butylamine to form perindopril erbumine, which is crystallized by heating the reaction mixture, filtering hot, cooling and finally filtering of the crystallized perindopril erbumine.
This patent gives a detailed description of synthesis of perindopril erbumine divided in three stages—one related to synthesis of (2S,3aS,7aS)-2-Carboxyoctahydroindole; second describing synthesis of N-[(S)-1-Carbethoxybutyl]-(S)-alanine and the third stage comprising reaction of the compounds obtained by stages one and two to give perindopril and perindopril erbumine thereof. The chemistry practiced therein is summarized in Scheme-I.

However, apart from the description of synthesis given therein the U.S. Pat. No. 4,914,214 does not provide any detail of the crystal nature of perindopril erbumine obtained.
In addition, the method utilizes solvents such as acetonitrile and 1,4-dioxane for crystallization/purification of the erbumine salt, which come under the category of Class II solvents as categorized by International Conference of Harmonisation (ICH). The guidelines recommend that such solvents i. e. belonging to Class II category should not be used or their use should be limited in a method for manufacture of a drug substance.
WO 01/58868 discloses a method for preparation of perindopril erbumine comprising reacting benzyl ester of (2S,3aS,7aS)-2-carboxyperhydroindole, p-toluenesulfonate salt with (S,S) diastereoisomer of N-[(S)-1-carbethoxybutyl]-(S)-alanine in the presence of 0.4 to 0.6 moles of 1-hydroxybenzotriazole; 1 to 1.2 moles of dicyclohexylcarbodiimide and 1 mole of triethylamine at 77° C. to give the dipeptide compound, which on debenzylation gives perindopril.

Example-3 of this patent application, describes a method for preparation of perindopril erbumine consisting refluxing a suspension of perindopril and tert-butylamine in ethyl acetate, followed by cooling the solution to 15-20° C. and isolating the crystallized product by filtration.
However, this application also does not provide any detail of the crystal nature of perindopril erbumine thus obtained.
EP 1 279 665 discloses N-carboxy anhydride of N-[1-(S)-ethoxycarbonyl-3-butyl-S-alanine (B), and a process for its preparation by reaction of N-[1-(S)-ethoxycarbonyl-3-butyl-S-alanine (A) with phosgene. The application further relates to a method for preparation of perindopril and perindopril erbumine using the said N-carboxy anhydride compound (B).
Claim 9 of this application recites a process for preparation of N-[1-(S)-ethoxycarbonyl-3-butyl-S-alanine (A), comprising reaction of a suitably protected alanine of formula (C) with a suitably functionalised pentanoic acid ester, in particular wherein the leaving group is a trifluroromethanesulfonyloxy (—OSO2CF3) group of formula (D) as summarized in Scheme-II.
It might be mentioned herein that the chemistry embodied in claim 9 of EP 1 279 665 is obvious and anticipated from similar chemistry reported by D. W. Payling et. al. in J. Med. Chem., 1991, 34, 430-447
Example-2 of this patent application, describes a method for preparation of perindopril erbumine consisting heating a mixture of perindopril and tert-butylamine in acetonitrile at 40° C., followed by cooling the solution to 5° C. and isolating the crystallized product by filtration. However, for reasons mentioned hereinearlier use of acetonitrile poses hazards in operability on a commercial scale.
Further, this application also does not provide any detail of the crystal nature of perindopril erbumine obtained.
Moreover, this method utilizes toxic and hazardous phosgene for preparation of the N-carboxy anhydride compound, thereby rendering it commercially unattractive.

WO 01/87835, WO 01/87836 and WO 01/83439, all having an international filing date of Jul. 6, 2001 and drawing priority from three French Applications, all in turn having a filing date of Jul. 6, 2000 claim three different crystalline forms of perindopril erbumine and a process for preparation thereof.
WO 01/87835 teaches a crystalline form, designated as the α crystalline form of perindopril erbumine, which is obtained by bringing to reflux a solution of the erbumine salt of perindopril in ethyl acetate and cooling the solution progressively or gradually till complete crystallization.
WO 01/87836 teaches a crystalline form, designated as the β crystalline form of perindopril erbumine, which is obtained by bringing to reflux a solution of the erbumine salt of perindopril in dichloromethane and cooling the solution rapidly to 0° C. and isolation of the solid obtained by filtration. Alternatively, the β crystalline form is prepared by bringing to reflux a solution of the erbumine salt of perindopril in ethyl acetate and cooling the solution rapidly to 5° C. and isolation of the solid obtained by filtration.
WO 01/83439 teaches a crystalline form, designated as the γ crystalline form of perindopril erbumine, which is obtained by bringing to reflux a solution of the erbumine salt of perindopril in chloroform and cooling the solution rapidly to 0° C. and isolation of the solid obtained by filtration. Alternatively, the γ crystalline form is prepared by bringing to reflux a solution of the erbumine salt of perindopril in ethyl acetate and cooling the solution rapidly to 5° C. and isolation of the solid obtained by filtration, followed by suspending the solid in chloroform and agitating at room temperature for 5 to 10 days, and collecting the solid by filtration.
From the foregoing, it would be apparent that:    i) Neither the product patent of perindopril i. e. U.S. Pat. No. 4,508,729 nor the majority of the large number of subsisting process patents, contain any enabling disclosure for preparation of perindopril and/or perindopril erbumine,    ii) Those patents, in particular U.S. Pat. No. 4,914,214, WO 01/58868 and EP. 1 279 665 that do disclose a method for preparation of perindopril and perindopril erbumine, however, do not specify the crystal nature of the product thus obtained,    iii) The only report wherein the crystalline nature of perindopril erbumine has been specified are contained in. WO 01/87835, WO 01/87836 and WO 01/83439, covering three distinct crystalline forms, designated as α, β, or γ forms respectively and a process for preparation thereof,
Thus, a need exists for a method of obtaining perindopril erbumine in a crystalline form conforming to that presumably existing in the marketed dosage form of ACEON® Tablets in a reproducible manner, which moreover, is obtained through utilization of solvents that are not frowned upon by regulatory authorities all over the world.